Renin release regulation during acute renin inhibition in normal volunteers.

Blockade of the renin-angiotensin system by an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (Ang II) antagonist is accompanied by a reactive rise in renin release. This rise is generally attributed to interruption of the short feedback loop between Ang II and renin release. Similarly, after the administration of a renin inhibitor, the plasma concentrations of active and total renin are increased and plasma renin activity is suppressed. The aim of the present study was to investigate if a fall in the plasma Ang II level is the unique determinant of the rise in the active renin (AR) level that follows renin inhibition. Six normal male volunteers participated in three successive 240-minute experiments at weekly intervals according to a single-blind randomized Latin square design. For experiment 1, Ang II was infused at 2 ng/kg/min from 0 to 60 minutes and at 4 ng/kg/min from 60 to 120 minutes. For experiment 2, 0.3 mg/kg of the new potent renin inhibitor Ro 42-5892 was injected at 30 minutes followed by infusion at 0.1 mg/kg/hr from 30 to 240 minutes. For experiment 3, Ang II and Ro 42-5892 were administered simultaneously at the same doses as described above. The mean +/- SEM Ang II concentration increased from 10.2 +/- 1.6 to 33.7 +/- 11.2 pg/ml after infusion of exogenous peptide. It decreased from 9.5 +/- 0.9 to 1.4 +/- 0.3 pg/ml after the injection of Ro 42-5892 and increased from 15.6 +/- 2.9 to 37.1 +/- 11.8 pg/ml after the simultaneous infusion of both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamics, biochemical effects, and pharmacokinetics of the renin inhibitor remikiren in healthy human subjects.

INTRODUCTION: Remikiren (Ro 42-5892) is a potent and specific inhibitor of human renin in vitro. Its in vivo action on plasma renin activity (PRA), immunoreactive renin, and blood pressure has been shown in pilot studies in humans. OBJECTIVE: To investigate tolerability, hemodynamic effects, and biochemical effects of remikiren in relation to its pharmacokinetics after single ascending intravenous and oral doses in healthy humans. METHODS: In this double-blind, placebo-controlled, two-way crossover (intravenous and oral) study, single ascending doses of 10, 20, 40, 80, 160, and 320 mg (intravenous) and 100, 200, 400, 800, and 1600 mg (oral) were given; six subjects received active drug and three received placebo at each dose level. At regular intervals, blood pressure, heart rate, cardiac output, PRA, immunoreactive renin, and drug plasma levels were determined. RESULTS: The compound was well tolerated except at the 1600 mg oral dose level at which diarrhea occurred in two subjects. At neither dose were there effects on blood pressure, heart rate, or cardiac output relative to placebo. PRA and angiotensin I production rate decreased and immunoreactive renin increased dose dependently after both intravenous and oral administration. The duration of these effects was also dose dependent and was longer than 12 hours with higher doses. Systemic plasma clearance, volume of distribution, and absolute bioavailability of remikiren were in the magnitude of 900 ml/min, 70 L, and below 1%, respectively. The angiotensin I production rate correlated in a sigmoidal way with plasma drug concentrations independent of the route of administration. CONCLUSION: Remikiren is a potent inhibitor of renin in humans with long-lasting effects after both intravenous and oral administration.

Nifedipine: influence of renal function on pharmacokinetic/hemodynamic relationship.

The hemodynamic effects and kinetics of nifedipine were examined in four groups of five subjects with different degrees of impaired renal function. In a randomized order, each subject received nifedipine by an intravenous infusion (4.5 mg in 45 minutes) and by mouth as a sustained-release tablet (20 mg). Plasma concentrations of nifedipine and urinary metabolite excretion were measured by liquid chromatography. Heart rate, blood pressure, forearm blood flow, and plasma norepinephrine levels were examined serially. After intravenous nifedipine infusion, the elimination t1/2 was 106 +/- 24 minutes in controls and increased gradually across the groups to 230 +/- 94 minutes in the group with severe renal impairment. In these same groups, the volume of distribution at steady state was 0.78 +/- 0.23 and 1.47 +/- 0.24 L/kg, but total systemic clearance did not differ. Plasma protein binding decreased from 96.0% +/- 0.5% in controls to 93.5% +/- 0.4% in severe renal insufficiency. Except for systemic clearance, kinetics were closely related to creatinine clearance, as was the urinary excretion of the main nifedipine metabolite. Except for systemic availability, which tended to decrease, the kinetics of nifedipine tablets were not influenced by the degree of renal failure. Hemodynamic effects after intravenous nifedipine could be fit to plasma concentrations under a sigmoidal model. When compared with control values, the maximal effect on diastolic blood pressure was more than doubled in severe renal failure. The inverse correlation between maximal effect on diastolic blood pressure and creatinine clearance (r = -0.68) was independent of pretreatment values. Neither free drug levels corresponding to 50% of the maximal effect on diastolic blood pressure nor the slope of the concentration-effect curve was influenced by the degree of renal impairment. The maximal effect on forearm blood flow tended to increase in renal failure, whereas the effect on heart rate was unchanged. Blood pressure changes after oral nifedipine were of the order of those after intravenous infusion. We conclude that, although nifedipine kinetics differ in patients with renal failure, these changes do not explain the greater blood pressure lowering effect.

Rate of increase in the plasma concentration of nifedipine as a major determinant of its hemodynamic effects in humans.

The relevance of the rate of increase in the plasma concentration of nifedipine for the drug's hemodynamic effect was investigated in healthy volunteers. Nifedipine was given intravenously according to two regimens, each designed to produce the same steady-state concentration, but attained gradually (within 5 to 7 hours) with one regimen and rapidly (within 3 minutes) with the other. The mean steady-state concentrations obtained were 31.7 +/- 5.2 (SD) ng/ml and 29.4 +/- 9.8 ng/ml, respectively (not significant). With the gradual regimen, heart rate was unchanged and diastolic blood pressure was lowered gradually by approximately 10 mm Hg. With the rapid regimen, heart rate increased immediately and remained elevated for the duration of the infusion, whereas diastolic blood pressure did not change significantly. At the end of the gradual-rise regimen, the infusion rate was increased tenfold for 10 minutes, promptly resulting in tachycardia and a paradoxical rise in diastolic blood pressure. These divergent hemodynamic responses of the gradual- and rapid-rise regimens could well be related to differences in baroreceptor activation. It is concluded that the hemodynamic response to nifedipine is influenced by the rate of increase of its concentration in plasma.

Nifedipine kinetics and dynamics during rectal infusion to steady state with an osmotic system.

Nifedipine steady-state kinetics and dynamics were investigated in a placebo-controlled study of six healthy subjects. Nifedipine was given rectally through an osmotic system at a zero-order rate for 24 hr. Steady-state plasma concentrations of approximately 20 ng/ml were achieved within 6 to 8 hr. Nifedipine lowered diastolic blood pressure (DBP) and increased forearm blood flow (FBF) and plasma norepinephrine concentration. On the other hand, heart rate (HR) and systolic blood pressure were not affected. Changes in DBP and FBF were closely related to nifedipine plasma concentrations during and immediately after the infusion period. Our data indicate that nifedipine lowers blood pressure in subjects with normotension and that it is possible by infusing the drug at a relatively low rate to dissociate its effect on blood pressure from that on HR.

Efficacy and tolerability of the renin inhibitor Ro 42-5892 in patients with hypertension.

The efficacy of multiple oral administration of the renin inhibitor Ro 42-5892 [(S)-alpha-](t-butylsulfonyl)-methyl]hydrocinnamamido]-N-[1S , 2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imi dazole-4- propionamide] was studied. Forty-nine patients with moderate essential hypertension were randomly assigned to three groups that entered an 8-day double-blind oral treatment period: daily administration of placebo (group A), 300 mg Ro 42-5892 (group B), or 600 mg Ro 42-5892 (group C). Four hours after the last oral drug intake, placebo was administered intravenously to subjects in group A and 100 mg Ro 42-5892 was administered intravenously to subjects in groups B and C. Sitting systolic and diastolic blood pressures were measured on days 1 and 8 with a blood pressure device. On day 1, systolic blood pressure maximally decreased by 13.3 +/- 9.3, 20.2 +/- 11.2, and 24.1 +/- 11.3 mm Hg in groups A, B, and C, respectively (mean +/- SD; p < 0.01 for group A versus group C). Diastolic blood pressure maximally decreased 9.4 +/- 5.7, 13.9 +/- 8.7, and 11.8 +/- 5.7 mm Hg (difference not significant). On day 8, systolic blood pressure maximally decreased 19.5 +/- 16.5, 26.5 +/- 17.4, and 30.5 +/- 18.4 mm Hg and diastolic blood pressure maximally decreased 14.8 +/- 5.0, 16.2 +/- 9.0, and 17.9 +/- 12.7 mm Hg (difference not significant) compared with pretreatment values. Intravenous drug administration did not further reduce blood pressure, suggesting that the mode of action and not the low bioavailability was the limiting factor for the low efficacy.

Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration.

The pharmacokinetics and hemodynamic effects of nifedipine were studied in patients with liver cirrhosis and in age-matched healthy control subjects. In a randomized order each subject received nifedipine by intravenous infusion (4.5 mg in 45 minutes) and as a tablet (20 mg). After intravenous nifedipine patients had a longer elimination t1/2 (420 +/- 254 vs. 111 +/- 22 minutes; P less than 0.01), a greater volume of distribution (1.29 +/- 0.60 vs. 0.97 +/- 0.42 L/kg), and a lower systemic clearance (233 +/- 109 vs. 588 +/- 140 ml/min; P less than 0.001). Plasma protein binding of nifedipine was lower in the patients (P less than 0.001). After oral nifedipine systemic availability was much higher in patients (90.5% +/- 26.2% vs. 51.1% +/- 17.1%; P less than 0.01) and maximal in patients with a portacaval shunt. Blood pressure decreased and heart rate increased after intravenous nifedipine and these effects could be fitted to plasma concentrations by a sigmoidal model. Maximal effects on heart rate and diastolic blood pressure were not different in liver cirrhosis. When free drug levels were considered, the concentrations corresponding to half the maximal effect were also not different. Blood pressure changes with oral nifedipine were comparable with those after intravenous infusion. We conclude that in patients with liver cirrhosis the pharmacokinetics of nifedipine are considerably altered; dose reduction is recommended when such patients need oral nifedipine.

In vivo tissue pharmacokinetics by fluorine magnetic resonance spectroscopy: a study of liver and muscle disposition of fleroxacin in humans.

Magnetic resonance spectroscopy of fluorine (19F) has been used to noninvasively study the in vivo pharmacokinetics of a model drug, fleroxacin (a fluoroquinolone antibiotic agent), in healthy human subjects. After oral administration, fleroxacin was detected in 19F magnetic resonance spectra from both liver and calf muscle and four magnetic resonance examinations were undertaken during a 24-hour period. By combining plasma analysis by high performance liquid chromatography with the magnetic resonance data, the following pharmacokinetic parameters (mean values) were obtained: tmax, 1.4, 4.6, and 5.6 hours in liver, plasma, and muscle, respectively; Cmax, 53, about 250, and about 60 mumol/L in plasma, liver, and muscle, respectively; t1/2, 4.4 hours (fast phase) and 10.8 hours (slow phase) in liver and 14.2 hours in plasma. The study documents for the first time the potential use of 19F magnetic resonance spectroscopy to noninvasively observe the time-related changes of a fluorine-containing drug in human tissues after oral administration.

Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension.

The tolerability and hemodynamic and humoral effects of the structurally novel calcium antagonist Ro 40-5967 were investigated in 64 patients with hypertension. In a double-blind, placebo-controlled study, ascending oral doses of 50, 100, 150, or 200 mg were administered once daily for 8 days in a solution. Ro 40-5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia. Blood pressure was dose-dependently reduced over the full 24-hour dosing period with more pronounced effects on day 8 than on day 1. The maximum blood pressure reduction was obtained after 150 mg (supine blood pressure, -34/-25 mm Hg, p less than 0.001). Despite a slight decrease in supine heart rate, cardiac output increased. PQ time was dose-dependently increased and concentration-effect analysis showed that relevant atrioventricular conduction disturbances occur only at concentrations much higher than those required to reduce blood pressure. Changes in catecholamines, plasma renin activity, and aldosterone were small and inconsistent. In conclusion, Ro 40-5967 has a long-lasting antihypertensive effect after once-daily administration.

Nifedipine: kinetics and dynamics in healthy subjects.

Kinetics and pharmacologic effects of three formulations of nifedipine were examined in six healthy young men in a crossover design. Each subject received intravenous nifedipine, 0.015 mg/kg body weight, 20 mg in a capsule, and 20 mg in a slow-release tablet. Changes in heart rate (HR), blood pressure, heart dimensions, and plasma norepinephrine levels (PNE) were examined serially. Plasma concentrations of nifedipine (Cp) and urinary metabolite concentrations were measured by liquid chromatography. After intravenous injection the elimination t1/2 was 1.7 +/- 0.4 hr, systemic clearance was 26.7 +/- 5.4 l/hr, and volume of distribution was 0.8 +/- 0.2 l/kg. After the capsule, Cp rose rapidly, to a maximum concentration (Cmax) of 117 +/- 15 ng/ml at a maximum time (tmax) of 1.4 +/- 0.5 hr. After the sustained release tablet tmax was 4.2 +/- 0.7 hr and Cmax was 26 +/- 10 ng/ml. Nifedipine bioavailability was 56% +/- 25% for the capsule and 52% +/- 13% for the tablet, but there were large interindividual differences. Urinary excretion was 58% +/- 13% 24 hr after intravenous injection, and after 32 hr was 55% +/- 13% after capsules and 32% +/- 8% after tablets. HR increased briefly after intravenous injection and after capsules (15 to 20 bpm), but not significantly after tablets. Diastolic blood pressure (DBP) fell briefly after capsules (8 to 10 mm Hg), but there was a sustained effect after tablets. Cardiac dimensions were unchanged. PNE levels paralleled plasma drug levels in the three experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Incremental dosage of the new antipsychotic mazapertine induces tolerance to cardiovascular and cognitive effects in healthy men.

OBJECTIVES: Mazapertine is a structurally novel antipsychotic compound with high affinity for D2, D3, 5-HT1a, and alpha 1 receptors. The objectives were to determine whether tolerance to orthostatic hypotension caused by this compound could be induced by slowly increasing the dose administered and to investigate its effect on cognitive and motor functions. METHODS: Thirteen healthy male subjects received incremental oral doses of mazapertine (from 5 to 50 mg over 7 days; n = 10) or placebo (n = 3) in part I and single doses in parts II (20 or 30 mg or placebo) and III (40 mg or placebo) in a double-blind fashion. Blood pressure, heart rate, cardiac hemodynamics, cognitive functions, and occurrence of acute extrapyramidal symptoms were investigated. RESULTS: Mazapertine appears to be safe and well tolerated when administered orally for 7 days to normal healthy men. No accumulation of serum prolactin occurred after multiple dosing, suggesting limited potential for inducing galactorrhea. The drug was rapidly absorbed, and kinetics appeared to be dose dependent, without accumulation. The elimination half-life was about 5 to 10 hours. No evidence of any positive or negative cognitive effects could be detected. Mild motor symptoms were observed only at high doses (not statistically significant). Mazapertine had a minimal effect on cardiac output and stroke volume. Tolerance to hypotension could be induced by slowly increasing the dose administered. CONCLUSIONS: Mazapertine is well tolerated when administered orally for seven days, and tolerance to hypotension can be induced by slowly increasing the dose administered. Therefore, nothing precludes further clinical testing on patients with schizophrenia.

Clinical pharmacology of cilazapril.

In clinical pharmacology studies cilazapril, after its bioactivation to cilazaprilat, was characterized as a potent, reversible angiotensin-converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours consistent with saturable binding to ACE. Despite the arterial vasodilation, only slight increases in heart rate were found. Cilazapril had no acute effect on cardiovascular reflexes. Cilazapril increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close and steep correlation between cilazaprilat plasma concentration and ACE inhibition was found. The potency of cilazaprilat, defined as the concentration of cilazaprilat causing 50 percent ACE inhibition, was approximately 1 ng/ml plasma. In short-term studies in hypertensive patients, it appeared that more than 90 percent of plasma ACE inhibition is needed to obtain blood pressure reduction. The result of various dose-response studies established the indirect relationship between dose, plasma concentration of the drug, and the blood pressure response and identified the dose producing maximal effect (i.e., 5 mg). Cilazapril had relatively long-lasting effects on ACE inhibition. In patients with severe chronic renal impairment or hepatic failure, the duration of ACE inhibition of cilazapril was prolonged. In these patients a reduction of the dose and/or less frequent dosing is recommended. There was no clinically relevant interaction of cilazapril with food or furosemide. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril. An additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with nonsteroidal anti-inflammatory drugs and cilazapril might occur, potentially reducing the blood pressure lowering effect. In general cilazapril was well tolerated.

Influence of the angiotensin converting enzyme inhibitor cilazapril, the beta-blocker propranolol and their combination on haemodynamics in hypertension.

This study compared the antihypertensive effects and the haemodynamic mechanisms of action of an angiotensin converting enzyme (ACE) inhibitor, a beta-blocker and the combination of both in patients with mild to severe hypertension. After a placebo run-in period of 2 weeks, patients were treated for 3 weeks with each of the following: cilazapril (2.5 mg daily) and propranolol (120 mg daily), in a randomized sequence, and thereafter a combination of the two drugs. Blood pressure, cardiac output (measured by Doppler ultrasound) and total peripheral resistance (TPR) in a sitting position at rest were determined. One patient out of 18 was withdrawn in the cilazapril phase. Both monotherapies yielded significant and similar reductions of diastolic blood pressure (average -10 mmHg). Cardiac output and TPR showed opposite effects. Cardiac output was lower with the beta-blocker than with the ACE inhibitor (3.4 versus 4.5 l.min-1), while TPR behaved conversely (2646 versus 2005 dyne.s.cm-5). The combination of both drugs lowered diastolic blood pressure significantly more than the monotherapies (average -20 mmHg); the haemodynamic effects of the monotherapies were attenuated by the combination (cardiac output = 3.7 l.min-1; TPR = 2170 dyne.s.cm-5). A sitting diastolic blood pressure of less than or equal to 90 mmHg could be achieved in six out of 17 patients with propranolol alone, in eight out of 18 with cilazapril alone, and in 14 out of 17 with the coadministration of both drugs. The combination was better tolerated subjectively than the beta-blocker alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and nephrotoxicity of cyclosporine in renal transplant recipients.

Pharmacokinetics of Cyclosporine (CsA) were studied in 14 renal transplant patients during a three-month period of treatment. At 3 and 15 days after transplantation 12-hr blood level studies of the drug were performed to calculate the elimination half-life, area under the curve (AUC), and total blood clearance; trough levels were measured twice weekly. In 9 patients terminal half-lives could be calculated after discontinuation of CsA treatment. In the course of CsA treatment, prolongation of half-life was found in most cases, with a significant decrease in clearance (46 +/- 17 L/hr on day 3 versus 28 +/- 10 L/hr on day 15). This resulted in a continuous increase in the CsA blood level. The terminal half-life varied considerably among the patients (24-93 hr) and did not correlate with other pharmacokinetic parameters. A good correlation (r = 0.9589) was observed between CsA trough levels before discontinuation of CsA and the increment in renal function two weeks after conversion to azathioprine. This indicates that short-term CsA treatment induces a dose-dependent reversible nephrotoxic effect in renal transplant recipients.

Angiotensin-converting enzyme inhibitors. Relationship between pharmacodynamics and pharmacokinetics.

The inter-relationship between the pharmacokinetic and pharmacodynamic behaviour of ACE inhibitors is reviewed. First, some of the methods which have been used to assess the pharmacodynamics of ACE inhibitors in humans are presented. They include humoral assays (e.g. ACE activity in plasma, renin activity, etc.), haemodynamic changes (blood pressure, total peripheral resistance, etc.) and agonist challenges (angiotensin I infusions). Subsequently a pharmacokinetic-dynamic model is described, based on biochemical processes obtained after ACE inhibition, which seems to be useful for the interpretation of the complex processes. The various correlations between plasma drug concentration on the one hand and plasma ACE activity, angiotensin II concentration in plasma or blood pressure on the other, are discussed on the basis of this model. From the model obtained it becomes obvious that under many circumstances the release of the inhibitor from ACE binding is the step which in fact determines the pharmacodynamically relevant elimination rate of the drug at low concentrations, whereas at high concentrations the elimination of the drug is mainly dependent on kidney (and/or liver) elimination rate. The dynamic-kinetic correlations are then presented for some ACE inhibitors in various disease states: arterial hypertension, heart failure, old age, renal failure, liver disease. In a final section the kinetic and dynamic relevance of interactions of ACE inhibitors with food and other drugs is described (e.g. prostaglandin inhibitors, diuretics, digoxin and cimetidine). Despite the great body of literature which deals with the kinetic and/or dynamic properties of ACE inhibitors, precise knowledge of the relationship between their kinetic and dynamic behaviour is rather limited and there is a clear need for further studies to elucidate this complex topic, thereby improving therapeutic possibilities with these useful new compounds.

Nifedipine. Relationship between pharmacokinetics and pharmacodynamics.

The availability of specific chemical assays and the development of appropriate biological models have made it feasible to study the relationship between the pharmacokinetics and the pharmacodynamics of nifedipine, a relationship that is presumed to be sigmoidal for most effects. In healthy volunteers the haemodynamic effects of a single dose of nifedipine are markedly influenced by the pharmaceutical preparation and the rate of drug input. When the plasma concentration of nifedipine increases rapidly, such as after an intravenous bolus injection or rapidly disintegrating capsules, there is a marked increase in heart rate and little or even no effect on blood pressure. On the other hand, when the drug is given as a slow intravenous infusion or as a sustained release tablet and when the capsules are taken together with food, the decrease in blood pressure is accompanied by few or no changes in heart rate. Furthermore, it has been shown that not only haemodynamic effects of nifedipine, but also oesophageal motor function may be used as a quantifiable pharmacological effect. For patients with angina pectoris, a plasma concentration range that is associated with optimal treatment has not been defined, since large inter-individual variations in the nifedipine plasma concentration were observed in effectively treated patients. For patients with hypertension, significant sigmoidally shaped correlations between blood pressure reduction and nifedipine plasma concentrations following single or multiple doses have been demonstrated. The concentration-effect parameters were very similar to those found for normotensive subjects. After 6 weeks of treatment the potency of the drug had decreased, which might indicate the development of some tolerance. In patients with severe renal impairment, the maximal effect of nifedipine on diastolic blood pressure was more than doubled, which cannot be explained by differences in pharmacokinetics; therefore these patients appear to be more sensitive at the pharmacodynamic level. In patients with liver cirrhosis, the pharmacokinetics of nifedipine were quite different due to reduced protein binding and reduced enzyme activity; in patients with a portacaval shunt, considerable increased bypassing of the liver during the first pass after oral administration was observed. When corrected for free drug concentrations, the concentration-effect relationship for these patients is essentially the same as that found for healthy subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of haemodialysis on the pharmacokinetics and haemodynamic effects of nifedipine during continuous intravenous infusion.

The pharmacokinetics and haemodynamic effects of nifedipine were studied in 5 patients on long term haemodialysis. In addition, clearance of the drug on 2 different types of artificial kidneys were measured in vitro. Nifedipine was administered intravenously (1.3 mg/h) from 6 hours before starting haemodialysis to the end of haemodialysis, performed according to the standard protocol of each patient. Before and during haemodialysis, blood samples were taken for determination of free and total plasma nifedipine concentrations. Recovery was determined by measuring nifedipine concentrations in the dialysate. Heart rate and systolic and diastolic blood pressures were determined serially. The haemodynamic changes during nifedipine were compared with those of 3 previous dialysis sessions. Haemodialysis was accompanied by a slight decrease in steady-state nifedipine concentrations. The recovery in dialysate varied between 0.6 and 0.9% of the amount infused during the period of dialysis. Artificial kidney clearance of nifedipine varied between 2.8 and 8.3 ml/min, which was in agreement with in vitro data. Changes in steady-state nifedipine concentrations were most likely due to changes in systemic clearance caused by haemodialysis itself. Systolic and diastolic blood pressure dropped by approximately 15% and 25%, respectively, in comparison with dialysis without nifedipine, but changes in heart rate were not different. It is concluded that nifedipine is poorly dialysable. During haemodialysis, blood pressure is markedly reduced but dose schedules need not to be changed.

Clinical pharmacology of cilazapril.

In clinical pharmacology studies, cilazapril, after its bioactivation to cilazaprilat, was characterised as a potent, reversible angiotensin converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours, which is consistent with saturable binding to ACE. Despite the arterial vasodilatation, only slight increases in heart rate occurred during cilazapril administration. Cilazapril had no acute effect on cardiovascular reflexes, and increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close positive correlation was found between the cilazaprilat plasma concentration and degree of ACE inhibition. The potency of cilazaprit, defined as the concentration of cilazaprilat causing 50% inhibition of ACE, was approximately 1 microgram/L plasma. In short term studies in patients with hypertension, it appeared that more than 90% inhibition of plasma ACE was needed to obtain blood pressure reduction. Results of various dose-response studies established the indirect relationship between dose, the plasma concentration of the drug, and the blood pressure response, and identified the dose producing the maximal effect to be 5mg. Cilazapril inhibited ACE for a relatively long period which was extended in patients with severe chronic renal impairment or hepatic failure. In these patients a reduction of the dose and/or less frequent administration is recommended. There was no clinically relevant interaction of cilazapril with food, furosemide (frusemide), digoxin or coumarins. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril, and an additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with indomethacin and cilazapril might occur, potentially reducing the blood pressure-lowering effect of cilazapril. In general, cilazapril was well tolerated.

Anti-D immunoglobulin in Rh(D) negative volunteers: clearance of Rh(D) positive red cells and kinetics of serum anti-D levels.

Properties of a new anti-D immunoglobulin were assessed in Rh(D) negative healthy male adults. Six volunteers received intravenous, and five volunteers intramuscular injections of 200 micrograms anti-D, 48 hours after pre-treatment with 5 mL of Rh(D) positive erythrocytes. Immediately after intravenous administration of anti-D, a rapid decrease of the Rh(D) positive erythroyctes was noted. After intramuscular injection of anti-D, there was a lag phase of 6 hours until the erythrocytes decreased, and the elimination rate was slower. Twenty-four hours after injection of anti-D, the Rh(D) positive erythrocytes were at the detection limit or no longer detectable in all volunteers. After intravenous administration, anti-D serum levels decreased from 45 ng/mL at 2 hours to 29 ng/mL at 24 hours, whereas after intramuscular administration, anti-D became detectable at 4 hours and increased to 11 ng/mL at 24 hours. During subsequent months, anti-D serum levels decreased at similar rates in both groups. After six months, anti-D was not detectable in any of the volunteers. Thus, the new anti-D immunoglobulin induced elimination of the Rh(D) positive erythrocytes and suggested that Rh(D) immunization of the volunteers was prevented.